Cycloalkanol derivatives



United States Patent 2,955,139 CYCLOALKANOL DERIVATIVES Bruno Hofer, Muncheustein, Basel. Land, Willy Stoll,

Basel, Switzerland, assignors to Geigy Chemical Corporation, New York, N.Y., a corporationrofi Delaware No Drawing. Filed Dec. 30, 1957, Ser. No. 705,759

Claims priority, application Switzerland Jan. 8, 1957 3 Claims. (Cl. Z60'617) The present invention concerns a process for the production of new cycloalkanol derivatives as well as compounds obtainable according to this process which have valuable pharmacological properties.

Cycloalkanol derivatives of the general formula:

Ill/OH HO\ /o\ CECH wherein X is a divalent radical selected from the group consisting of CH -CH and OHOH2 and R represents an alkyl radical having from 1 to 4 carbon atoms,

HO O X CH og (II) wherein R and X have the meanings given above, with a mono-metal organic derivative of acetylene, in particular a mono-metal acetylide or an acetlye-ne mono-magnesium halide. In the former case, the condensation is performed, for example, in liquid abs. ammonia or in anhydrous organic solvents such as methylal, diethyl ether or mixtures thereof, formamide, dimethyl sulphoxide or dimethyl form-amide. Alkali metal acetylides can be used in particular as monometal acetylides. They are formed for example in situ either before the reaction by reacting acetylene with the metals dissolved in ammonia or they are formed during the reaction. In the latter case, for example acetylene is reacted with the ocketol in an organic solvent in the presence of a finely suspended alkali metal hydroxide under normal or slightly raised pressure, e.g. at 1.0 to 1.33 atmospheres.

As mono-metal organic derivative of acetylene, an acetylene mono-magnesium halide may also be reacted with an a-hydroxy-ketone of the general Formula II defined above in a suitable ether-like solvent such as tetrahydrofurane. A suspension of the Grignard component in tetrahydro' furane is obtained, for example by the addition in portions of a solution of ethylene magnesium bromide in tetrahydrofurane to a saturated solution of acetylene in tetrahydrofurane While continuously introducing acetylene (E. R. H. Jones, L. Skattebol and M. C. Whiting, J. Chem. Soc., 1956, 4765-58). In this case, the further addition of .the magnesium compound is only made on completion i'of the-development of ethane and renewed saturation of the reaction mixture with acetylene, so that there is always an excess of acetylene.

The presence of a free hydroxyl group in the ketone component naturally means that at least a molar excess of both the metal acetylide as well as acetylene magnesium halide must be used.

The a-ketols of the general Formula H in which R represents the methyl group necessary as starting materials are obtained for example by condensing cycloaliphatic ketones with alkali metal acetylides and adding water to the ethinyl-cycloalkanols obtained. In addition, the reaction described by Billimoria et al. (J. Chem. Soc., 1951, 3067) of u-hydroxycarboxylic acids with methyl lithium is mentioned.

Starting materials of the general Formula II containing an alkyl radical R having 2-4 carbon atoms are obtained from the cyanohydrins of suitable cycloaliphatic ketones. These are, for example, acylated or reacted with dihydropyrane or a vinyl ether to protect the hydroxyl group. The resultant l acyloxy-l-tetrahydropyranyloxyor l-(a alkoxy ethoxy) cycloalkane carboxylic acid nitriles can be reacted with low molecular alkylmggnesium halides to form imines from which the whydroxy-ketonespf the general formula II are obtained by hydrolysis. Examplesaof h compounds are 1- acetyl-, 1-propionyl-, l-butyrylandsl-isobutyrylcyclopentanol and 1-acetyl-methylcyclopentanol. n

The following example further illustrates the produc tion of the new compounds. The temperatures are given in degrees centigrade.

Example ml. of abs. ammonia are placed in a 350 ml. flask fitted with a condenser, stirrer, toluene thermometer, tube for the introduction of gas and dropping funnel and the flask, in a carbon dioxide/acetone bath, is cooled to -40. First 0.1 g. of crystallised ferric nitrate and then 0.4 g. of sodium are then added at 40 to 50. After the colour which was at first dark blue has changed to grey a further 4.6 g. of sodium are added in small pieces. When the dark blue colour has again changed to grey the whole is stirred for another half hour. About 5 litres of abs. acetylene gas are then introduced and then 12.8 parts of l-acetylcyclopentanol in 20 ml. of abs. ether aer added dropwise within 10 minutes While still introducing acetylene. On completion of the dropwise addition the whole is stirred for another hour under continous introduction of acetylene. The temperature is then raised to about 20 within 10-15 hours the mass being kept stirrable by the addition of abs. ether.

The reaction mixture is stirred for 2 hours under reflux of the ether, 5 0 ml. of saturated ammonium chloride solution are added at 0 and the reaction product is hydrolysed whereupon the reaction is made acid to Congo red paper with 50% sulphuric acid. It is taken up in ether, the etheral solution is washed neutral and dried over magnesium sulphate and concentrated. On distilling the residue in the vacuum, 3 methyl-4.4-tetramethylone-3.4-dihydroxy-butine-(1) is obtained. B.P. 117- 118.

Starting from l-butyryl-cyclopentanol, 3-propyl-4.4- tetramethylene-Z.4-dihydroxy-butine-(1) is obtained in an 3 analogous manner, 7, and" 1-[1'-hydroxy-2'-methy1-cyclopentyl-(l) ]-1-hydroxy1 methyl propine (2) (B.P. 114-117 in an analogous manner from 1acety1-2- methyl-cyclopentanol.

,Weclaimx 7 r ;1 A 3,- alkyl 4.47- tetramethylene 3.4 dihydroxybutine-(I) of hte formula wherein R represents an alkyl radical having from 1 to 4 carbon atoms inclusive.

2. 3-propy1-4.4-tetramethy1ene-3.4 dihydroxy hutine- 1 5 3. 3-methy1-4.4-tetramethy1ene-3.4 dihydroxy bufine- References Cited irr the 1115 of this patent i Henbest et al.; 10111". Chem. Soc (London) (1949), 10 pages 26964 700 (5 pages).

Nikitin et a1.; Chem Abstracts,

Vol. 47, (1953), col. 12,240 (1 page). 

1. A 3 - ALKYL - 44 - TETRAMETHYLENE - 3.4 - DIHYDROXYBUTINE-(1) OF THE FORMULA 